Distribution of Genetic Factors Associated with Severe COVID-19 in Ethnic Groups of the Eastern Caucasus

Background. Previously, genetic markers rs11385942 G>GA and rs657152 C>A of disease severity were identified for COVID-19. The study of the prevalence of clinically significant genetic markers may be useful for the development of region-specific approaches to disease control, considering, among other things, the ethnic composition of the territory, which is especially relevant for Russia. Based on the ethnic heterogeneity of the population of the Republic of Dagestan, this region was chosen as an example to study the distribution of COVID-19 severity markers of interest. Objective. Investigation of the prevalence of rs11385942 G>GA and rs657152 C>A markers among five ethnic groups residing in Dagestan. Methods. The study included 605 healthy volunteers (158 men and 447 women) from five different autochthonous ethnic groups living in the Republic of Dagestan: 118 Avars, 121 Dargins, 116 Laks, 127 Kumyks, and 123 Lezgins. Blood served as a material for determining polymorphisms. Carriage of polymorphic markers was determined by real-time polymerase chain reaction method. Results. The prevalence of rs11385942 G>GA marker ranges from 10.17% among Avars to 15.04% among Lezgins; significant differences were found in comparison with Russian ethnic group from literature sources. The second marker – rs657152 A>C — is distributed relatively homogeneously in the studied groups, without significant differences, and correlates with the data on the frequency of marker detection among Russians, as well as among European populations and worldwide — 50–60%. Conclusion. No differences were found within the ethnic groups of Dagestan in the carriage of both studied COVID-19 severity markers. At the same time, the rs11385942 G>GA marker detection frequency in the analyzed groups was on average higher in comparison with Russians and the average values for European populations.

1. Panel' VOZ po koronavirusu (COVID-19). URL: https://covid19.who.int/table (data obrashcheniya 09.07.2023)

2. He F., Deng Y., Li W. Coronavirus disease 2019: What we know? J Med Virol. 2020; 92 (7): 719–725. doi: 10.1002/jmv.25766.

3. Chen N., Zhou M., Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020; 395 (10223): 507–513. doi: 10.1016/S0140- 6736(20)30211-7.

4. Yang X., Yu Y., Xu J. et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020; 8 (5): 475–481. doi: 10.1016/S2213-2600(20)30079-5.

5. Shahid Z., Kalayanamitra R., McClafferty B. et al. COVID-19 and older adults: what we know. J Am Geriatr Soc. 2020; 68 (5): 926–929. doi: 10.1111/jgs.16472.

6. Wu Z., McGoogan J.M. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020; 323 (13): 1239–1242. doi: 10.1001/jama.2020.2648.

7. Phan L.T., Nguyen T.V., Luong Q.C. et al. Importation and human-tohuman transmission of a novel coronavirus in Vietnam. N Engl J Med. 2020; 382 (9): 872–874. doi: 10.1056/NEJMc2001272.

8. Evropejskij tsentr po profilaktike i kontroljyu zabolevanij. URL: https://www.ecdc.europa.eu/en/covid-19-pandemic (data obrashcheniya 12.07.2023)

9. Ghasemian R., Shamshirian A., Heydari K. et al. The role of vitamin D in the age of COVID-19: A systematic review and meta-analysis. Int J Clin Pract. 2021; 75 (11): e14675. doi: 10.1111/ijcp.14675.

10. Rhodes J.M., Subramanian S., Laird E. et al. Perspective: Vitamin D deficiency and COVID-19 severity — plausibly linked by latitude, ethnicity, impacts on cytokines, ACE2 and thrombosis. J Intern Med. 2021; 289 (1): 97–115. doi: 10.1111/joim.13149.

11. Severe Covid-19 GWAS Group; Ellinghaus D., Degenhardt F., Bujanda L. et al. Genomewide Association Study of Severe Covid-19 with respiratory failure. N Engl J Med. 2020; 383 (16): 1522–1534. doi: 10.1056/NEJMoa2020283.

12. Mirzaev K.B., Fedorinov D.S., Ivashchenko D.V., Sychev D.A. Multi-Ethnic analysis of cardiac pharmacogenetic markers of cytochrome P450 and membrane transporters genes in the Russian population. Rational Pharmacotherapy in Cardiology. 2019; 15 (3): 393–406. doi: https://doi.org/10.20996/1819-6446-2019-15-3-393-406. (in Russian)

13. Mirzaev K.B., Fedorinov D.S., Akmalova K.A. et al. Analysis of carrying clinically significant allelic variants of TPMT and DPYD genes associated with the response to drug therapy in cancer practice among 9 ethnic groups of the Russian Federation. Terapevticheskii Arkhiv. 2020; 92 (8): 43–51. doi: https://doi.org/10.26442/00403660.2020.08.000719. (in Russian)

14. Tang H., Quertermous T., Rodriguez B. et al. Genetic structure, selfidentified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet. 2005; 76 (2): 268–275. doi:10.1086/427888.

15. Balanovsky O., Petrushenko V., Mirzaev K. et al. Variation of genomic sites associated with severe Covid-19 across populations: global and national patterns. Pharmgenomics Pers Med. 2021; 14: 1391–1402. doi: 10.2147/PGPM.S320609.

16. Fink-Baldauf I.M., Stuart W.D., Brewington J.J. et al. CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1. EBioMedicine. 2022; 75: 103806. doi: 10.1016/j.ebiom.2021.103806.

17. Zhao J., Yang Y., Huang H. et al. Relationship between the abo blood group and the coronavirus disease 2019 (COVID-19) susceptibility. Clin Infect Dis. 2021; 73 (2): 328–331. doi: 10.1093/cid/ciaa1150.

18. Zietz M., Zucker J., Tatonetti N.P. Associations between blood type and COVID-19 infection, intubation, and death. Nat Commun. 2020; 11 (1): 5761. doi: 10.1038/s41467-020-19623-x.

19. Steffen B.T., Pankow J.S., Lutsey P.L. et al. Proteomic profiling identifies novel proteins for genetic risk of severe COVID-19: the Atherosclerosis Risk in Communities Study. Hum Mol Genet. 2022; 31 (14): 2452–2461. doi: 10.1093/hmg/ddac024.

20. Murray G.P., Post S.R., Post G.R. ABO blood group is a determinant of von Willebrand factor protein levels in human pulmonary endothelial cells. J Clin Pathol. 2020; 73 (6): 347–349. doi: 10.1136/jclinpath-2019-206182.

21. Valenti L., Griffini S., Lamorte G. et al. Chromosome 3 cluster rs11385942 variant links complement activation with severe COVID-19. J Autoimmun. 2021; 117: 102595. doi: 10.1016/j.jaut.2021.102595.

22. Orlova E.A., Ogarkov O.B., Khromova P.A. et al. SNP rs657152 Is not associated with the level of viral load in COVID-19 or the probability of disease in the population of caucasians in Eastern Siberia. Russ J Genet. 2021; 57 (8): 982–984]. doi: https://doi.org/10.31857/ S0016675821080099. (in Russian)

23. Marçalo R., Neto S., Pinheiro M. et al. Evaluation of the genetic risk for COVID-19 outcomes in COPD and differences among worldwide populations. PLoS One. 2022; 17 (2): e0264009. doi: 10.1371/journal.pone. 0264009.

24. Statistika rasprostraneniya koronavirusa v Respublike Dagestan. URL: https://coronavirus-monitor.info/ country/russia/respublika-dagestan/ (data obrashcheniya 15.07.2023)

25. Natsional'naya biblioteka meditsinskikh nauk SShA. URL: https://www.ncbi.nlm.nih.gov/snp/rs11385942/#frequency_ tab (data obrashcheniya 10.08.2023)